The risk of End Stage Renal Disease (ESRD) due to diabetes has tripled in recent decades. This has occurred despite widespread implementation of treatment with antihypertensive drugs and ACE inhibitors. This epidemic of ESRD is due to a real increase in the proportion of diabetic patients developing renal function loss rather than a consequence of improved survival of these patients. To contain this epidemic, research efforts are urgently needed to identify the determinants and mechanisms of renal function loss in diabetes so that new preventive programs can be developed. Particularly lacking is knowledge about the initiation and promotion of the early renal function decline. Recently, we found that renal function begins to decline in a large proportion of patients with type 1 diabetes once microalbuminuria (MA) develops. This early renal function decline was unrelated to further increases in the level of urinary albumin excretion but was associated with elevated levels of urinary chemokines. Preliminary proteomic analysis of urine from these patients revealed the presence of specific proteins in the urine of individuals with MA and early renal function decline that were absent in the urine of individuals with MA and stable renal function. These unknown urinary proteins represent candidates for exposures that injure the proximal tubules of patients with MA and are responsible for the elevated urinary chemokines. We aim to identify the proteins most associated with early renal function decline. Furthermore, we propose to use methods of proteomic analysis to characterize the urinary chemokines that distinguish patients with MA who are at risk of early renal function decline from those with stable renal function. These questions will be examined in both type 1 and type 2 diabetes. The Specific Aims of this proposal are: 1) To determine the frequency of significant early renal function decline in two cohorts of individuals with MA and type 1 diabetes (n=300), and type 2 diabetes (n=500). 2) To identify urinary protein(s) that cause early renal function decline in both cohorts by comparing urinary protein profiles between cases with early renal function decline and controls with stable renal function using proteomics analysis based on mass spectrometry. 3) To identify urinary and plasma cytokine/chemokine profiles that predict early renal function decline in the two cohorts using a targeted proteomics approach and Luminex technology. 4) To develop an etiologic model of early renal function decline in individuals with type 1 and type 2 diabetes and MA incorporating all the findings from these studies. The proposed research on the mechanisms and determinants of early renal function decline is novel and will provide data for the development of effective methods of prevention of renal function loss in diabetes. [unreadable] [unreadable]